Impact of genetic variations and transcriptional alterations of HLA class I genes on cervical cancer pathogenesis

다국어 초록 (Multilingual Abstract)

In a novel attempt to understand the variations in DNA sequences underlying HLA class I alleles associated with HPV16‐related CaCx, we determined the alleles by reconstructing SNP‐based haplotypes from resequencing of the most polymorphic exons 2 and 3 of HLA‐A, HLA‐B and HLA‐C. We also determined the impact of SNPs and transcriptional alterations of the genes on CaCx. A high density of SNPs was identified from resequencing. HLA expression was determined by real‐time PCR. We identified that even a single associated HLA allele had many underlying SNP‐based haplotypes. Out of the most frequent (≥5%) HLA class I alleles, HLA‐B*40:06 and HLA‐B*15:02 respectively imparted significant risk towards and protection from CaCx as well as HPV16 infection. Employing median‐joining networks to detect clusters of sequence‐variations for specific HLA alleles, we found the protective SNP‐based signature, GAATTTA, in all SNP‐based haplotypes of HLA‐B*15:02 allele. The signature was derived from seven SNPs within HLA‐B which were newly associated with the disease. Contrarily, similarly derived risk‐signature, TTGCGCC, mapped only to 52% of SNP‐based haplotypes of HLA‐B*40:06 allele. This indicated that all SNP‐based haplotypes underlying a particular associated HLA allele might or might not have a single signature of risk/protection. HLA‐A, HLA‐B and HLA‐C expressions were downregulated among CaCx cases compared to asymptomatic infections and HPV‐negative controls. HLA‐A and HLA‐B were repressed in both cases harbouring episomal and integrated HPV16, whereas HLA‐C in only the latter. Novel genetic variations and differential downregulation‐patterns of HLA class I have a significant bearing on HPV16‐related CaCx pathogenesis.
What's new?
Variations in human leukocyte antigen (HLA) genes are suspected of altering human papillomavirus (HPV) antigen presentation, potentially increasing or decreasing risk of cervical carcinoma (CaCx). The degree to which different HLA alleles influence CaCx development, however, is unclear. This analysis of single nucleotide polymorphisms (SNPs) and SNP‐based haplotypes reveals the existence of numerous underlying variations among CaCx‐associated HLA class I alleles. Of the most frequent alleles, however, only HLA‐B*40:06 was significantly associated with CaCx risk and HLA‐B*15:02 significantly linked to protective effects. Analyses further revealed varying patterns of downregulation in HLA‐A, HLA‐B, and HLA‐C expression, among HPV16‐positive CaCx samples with respect to HPV16 genome‐integration.